American Diabetes Association 76th Scientific Sessions

June 10-14, 2016; New Orleans, LA; Full Report – Themes – Draft

Executive Highlights

In this report, we provide our diabetes technology, diabetes drugs, and additional topics themes from the ADA’s 76th Scientific Sessions held at the New Orleans Ernest N. Moral Convention Center from June 10-14, 2016. This very successfully organized ADA gathering drew over 16,000 attendees, including 13,265 clinicians. Total attendance was down noticeably from over 18,000 last year in Boston, presumably due to location. A striking 58% of registered attendees were from outside the US in 2016, with over 120 countries represented.

Major drug highlights included the full LEADER (Novo Nordisk’s GLP-1 liraglutide) results showing a 13% risk reduction for the primary MACE endpoint, renal outcome results from EMPA-REG OUTCOME (Lilly/BI’s empagliflozin) demonstrating a 39% risk reduction for new-onset or worsening kidney disease, and favorable A1c results from SUSTAIN 2 and 3 (Novo Nordisk’s semaglutide. We also heard plenty on the future directions for type 2 drugs (particularly the GLP-1 class) and the use of SGLT-2 inhibitors in type 1 diabetes.

In technology, we were impressed to see positive results from three important studies for the field: Medtronic’s Minimed 670G pivotal trial, Dexcom’s DIaMonD study testing CGM in MDI, and Abbott’s FreeStyle Libre IMPACT study. We got a very deep dive on automated insulin delivery at this ADA, just as the field is on the cusp of commercialization. It was also great to see progress on making diabetes data more actionable through several industry updates (Ambulatory Glucose Profile, Medtronic Diabetes, IBM Watson).

Bigger picture, there was lots of talk about cost and inequity at this ADA, the major limitations of using A1c, the promise of precision medicine, and what the ADA’s role should be in the field. It was not a major year for obesity data, though there was promising data on the potential of type 2 drugs to make a difference.Below, we bring you our comprehensive themes summarizing the high-level trends and notable takeaways from ADA 2016.

Themes

Diabetes Technology

Automated Insulin Delivery

  • The AID (Automated Insulin Delivery) field is now moving into the commercialization stage. Will the first hybrid closed loop system, Medtronic’s MiniMed 670G/Enlite 3, be on the US market by ADA 2017?! Medtronic reported strong 670G pivotal study results at ADA (see below), and an FDA submission is planned before the end of this month (June 2016). FDA’s Dr. Courtney Lias even expressed hope during ADA that the review will be quick, and the company’s pre-ADA Analyst Meeting maintained the US launch timing by April 2017. Usability will be key – one never knows exactly what the difference will be between using a technology “in the wild” (also known as real life) vs. in a very well managed clinical trial without a parallel control group. Hopes are high … key opinion leaders are also talking about 2017 commercialization for the 670G, meaning next year could be the year it all starts.
    • Meanwhile, commercial systems from 6+ companies are gearing up for pivotal studies in the next ~6-18 months. Six! Animas, Tandem, TypeZero/International Diabetes Closed Loop Consortium (IDCL), Beta Bionics, Bigfoot Biomedical, Insulet, and others have all announced pivotal study plans with commercial devices (roughly in pivotal trial order), which will make the next couple of years very competitive and exciting for this field. (See our competitive landscape here.) It’s been a fast turnaround from ADA 2015, where the 670G pivotal study was only beginning, and a transformative leap from ADA 2014, where the AID discussion focused nearly exclusively on academic systems.
  • Medtronic headlined the AID discussion at ADA, presenting very positive results from the first pivotal study of a commercial system, the MiniMed 670G/Enlite 3 hybrid closed loop. The single-arm, three-month study in 94 adults and 30 adolescents compared a two-week open-loop run-in period to 90 days on the 670G, showing a 0.5% reduction in A1c from a low study baseline of 7.4%; time <70 mg/dl declining 44% (from 6% to 3%); and time <50 mg/dl declining 40% (1% to 0.6%). It was impressive to see the impact on A1c, given the strong reduction in hypoglycemia and the very well-controlled population of pumpers. (We note that the pumpers were spending only 7% of the time below 70 mg/dl – that’s pretty great control to begin with.) Notably, those with a baseline A1c >7.5% actually saw a 1% reduction after three months on the 670G. Time-in-range (71-180 mg/dl) improved from 67% during the baseline run-in to 72% during the study, with time >180 declining moderately (27% to 25%). That improvement does not sound so significant, but it was clear from the glucose profiles that the MiniMed 670G made extreme highs (e.g., 300 mg/dl) more moderate (e.g., ~200 mg/dl) – a highly valuable improvement, but not showing up as a change to time in 70-180 mg/dl. The glucose profiles (see below) show how the 670G really tightened the range of glucose values throughout the entire day in both populations, with particularly strong efficacy overnight and in adolescents. The new Enlite 3 sensor is a definite improvement, with an overall MARD of 10.3% in this study and 10.5% in its separate pivotal accuracy study.
    • Overall, we see the 670G pivotal data as meaningful for the entire field of automated insulin delivery. This single-arm, uncontrolled study was clearly designed for speed and to prove safety to the FDA, so it’s hard to read too much into the efficacy results, where there were not pre-specified endpoints. Still, reducing A1c 0.5% in well-controlled patients at the same time hypoglycemia declining 44% is a huge win – and the results were consistent in adolescents and adults. It’s clear that automated insulin delivery can make a difference even with first-gen hybrid closed loop products, and even in those doing pretty well. Of course, the hope is it can really improve outcomes for those with much higher A1cs as well (for example, over >10%) or at high risk of severe hypoglycemia, groups that were both excluded from this study.
    • Stanford’s Dr. Trang Ly characterized the 670G results as “outstanding,” and said that the biggest challenge will be managing expectations: “This is not going to cure you,” she noted, as the first-gen 670G algorithm is still somewhat conservative, and hybrid systems like the 670G will still require patient effort – to be specific, carb counting, manual corrections, infusion set changes, sensor wear and calibrations, etc. The 670G algorithm itself has ten years of work behind it, but since it only modulates basal insulin delivery, it will be most efficacious overnight, and it will clearly not remove all patient burden during the day. We expect to hear more on the 670G’s usability and user-friendliness as it gets closer to market.
  • Like so many other products, we expect those automating insulin delivery will improve with time, and the key will be in consistently improving the benefit-burden balance to expand the market. What will AID add onto patients’ and providers’ plates, and what will it remove? How will this balance vary based on what patients are already using – e.g., current pump-CGM users vs. MDI-SMBG users – and how will it change as insulins continue to improve, Bluetooth pens emerge, and standalone CGM sees better value with enhanced apps?
    • First-gen AID technology will likely be an upgrade for many current pump-CGM users, though the bar will be high for MDI-SMBG users – going from zero to two devices on the body will increase burden and cost, which means the corresponding improvement in outcomes needs to be big. For how many will that be worth it with gen one, gen two, etc.? What percentage of MDIs will ultimately wear AID systems?
    • What will most differentiate closed loop systems in a few years: outcomes/reimbursement, form factor, user interface, algorithms, other hormones, etc.? What will the adoption curve look like in five or ten years? What feature(s) will be the killer app(s) for AID that drive adoption – Full automation without meal announcement? Factory calibrated CGM? Smaller on-body devices? Integrated CGM/pump infusion sets? Will AID ever become standard of care in type 1? Will this technology appeals to MDIs that are struggling to manage blood glucose?
  • The nuances of pivotal study design, standardizing outcome metrics, the reimbursement landscape, and the psychosocial impact are now top of mind in the field. Though these have always been in the discussion, all emerged as themes at JDRF’s annual Closed-Loop Research Meeting as well as in countless Closed Loop discussions, and all reminded us that the commercial side of closing the loop presents awesome design opportunities and nuanced challenges. Which system(s) and companies will nail these aspects in the coming years?
    • Pivotal Study Design: MGH’s Dr. Steven Russell summarized a soon-to-be-published Diabetes Care paper he co-authored with Dr. Roy Beck, sharing pivotal study design recommendations for AID systems – this will be fantastic to see! Drs. Beck and Russell recommend broad study inclusion criteria (MDIs included, wide age and A1c ranges), use of A1c and time <60 mg/dl as primary endpoints, a parallel group design (faster), 6-12 months in length, and compared to usual care. Pivotal AP studies have several goals besides regulatory approval – advantageous labeling, reimbursement, prescribing by practitioners, and adoption by patients – meaning study design decisions now will be critical down the road.
    • Reimbursement: Avalere Health’s Amanda Bartelme gave a fascinating overview of AID reimbursement, highlighting some of the key challenges: too much payer focus on A1c, hard-to-predict contracting negotiations, data needs that differ from FDA approval requirements, and more. Ms. Bartelme cautioned that “if a payer thinks every type 1 patient wants to go on this tomorrow, that’s huge dollar signs and huge panic.” It served as a reminder that nothing is a given with payers in this environment – even AID devices that reduce A1c, hypoglycemia, and patient burden will have to demonstrate return-on-investment, and ideally, short-term. Q&A sessions throughout the conference also expressed worry about AID reimbursement, as many clinicians are still battling payers to even cover CGM. From what we can tell, Medtronic will pursue the existing reimbursement channels for the MiniMed 670G (i.e., sensor-augmented pump reimbursed via DME), though this field seems ripe for a new business model (e.g., AID for $75 a month).
    • Standardizing Outcomes Metrics: Barbara Davis Center’s Dr. David Maahs (soon to be at Stanford) summarized another upcoming Diabetes Care paper focused on standardizing a short set of basic, easily interpreted outcomes in artificial pancreas studies. The paper has 24 authors, many of whom are considered leading thinkers in the field. The goal is for the entire field to report study outcomes the same way, easing interpretation, enabling basic comparison between studies, and accelerating adoption via regulators, HCPs, payers, and patients. We love this move!
    • Psychosocial impact: Stanford’s Dr. Korey Hood shared that a full set of validated questionnaires will be available by Fall 2016 to assess the psychosocial impact of automated insulin delivery. There are high expectations that AID will help manage glycemia and improve quality of life, but the field is still in need of tools to help regulatory approval bodies, payers, HCPs, and patients assess systems’ full benefit-risk balance. How do we measure better quality of life due to less diabetes-related stress or better sleep? As insulin delivery becomes automated, how do we protect against deskilling and human-machine interaction failures and confusion? What is the stigma associated with carrying extra devices in those not currently using a pump or CGM? Experiences will fall along a spectrum, of course, but these are critical questions as AID systems are on the cusp of commercialization. We hope these new questionnaires can help add context to the non-glycemic benefits of AID systems, and perhaps identify those that are optimal candidates for the technology. Our greatest hope is that AID massively improves outcomes and quality of life in those struggling on current therapies, whether they are using MDI, pump, SMBG, or CGM.
  • Many called for closed-loop devices to include algorithms with customizable glucose targets. A patient panel at Diabetes Mine’s D-Data Exchange was clear that adjusting an algorithm’s aggressiveness is very key – some patients want more control, particularly in early-generation systems that will err on the conservative side. Indeed, Stanford’s Dr. Trang Ly pointed to this as an area for improvement in the Medtronic MiniMed 670G, which targets 120 mg/dl and does not allow the user to lower the target. The Bionic Pancreas team’s work comparing insulin-only to bihormonal control at different glycemic targets echoes the same point – an algorithm’s target does influence mean glucose and hypoglycemia, sometimes significantly so. Of course, there is a tough balance between customizability and simplicity – tweaking every parameter might be ideal for early adopters, but will add too much complexity that could hinder adoption. It’s a very delicate equilibrium, though targets will certainly go down over time as insulins get faster, sensors improve further, and the FDA and companies get more comfortable with these systems. It will be interesting to compare different commercial systems’ algorithms once they are available, as there may be meaningful differences in aggressiveness, meal announcement burden, initialization and training requirements, alarms, level of adaptation, and more.
  • ADA 2016 shed the most light yet on OpenAPS, the DIY automated insulin delivery system created by Ben West, Dana Lewis, and Scott Leibrand. The community now has 80 users and has over 150,000 hours of AID use outside any clinical trial setting. An illuminating late-breaking poster presented fascinating data from 18 out of the first 40 OpenAPS users. Self-reported outcome measures showed median A1c dropped from 7.1% to 6.2%, an impressive 0.9% reduction in a well-controlled and motivated population. Self-reported median percent time-in-range (80-180 mg/dl) increased from 58% to 81%. Fourteen out of 15 respondents reported some improvement in sleep quality, and 56% reported a large improvement. Respondents were “extremely satisfied with the “life changing” improvements associated with using an APS,” even if they “require significant effort to build and maintain” and “cannot be considered a technological cure.” Though such “hacked together” DIY systems are often perceived as unsafe, the OpenAPS design considerations posted here show how it is designed for safety (e.g., only temporary basals, no automatic correction boluses, etc. – much like the 670G hybrid closed loop).
    • The “unapproved” OpenAPS concerned some clinicians at ADA. Overall, the small community left us with positive takeaways for the field: (i) automated insulin delivery can make a huge glycemic and quality of life difference, even for well-controlled patients; (ii) even though this DIY system is burdensome to set up and wear, patients would not do it and use it unless the benefits were worthwhile (hopefully a good sign for fully integrated commercial systems); (iii) lots of learning is occurring in the OpenAPS community that could be leveraged for commercial systems; (iv) OpenAPS could push the FDA and industry to move faster, and that is a good thing; and (v) the relative risks here seem low, given the involved burden of setup, the solid design for safety, and the real-world dangers of insulin therapy. 
  • Some of the most compelling AID data came from the Cambridge team, who tested their system in inpatient type 2 diabetes – the first of this kind of closed-loop study ever done. The study shared striking improvements in efficacy and safety vs. the truly grim standard of care achieved with open-loop in the hospital. The parallel-arm study randomized 24 patients to receive either closed-loop therapy (n=12) or conventional subcutaneous insulin therapy per clinical guidelines with masked CGM (n=12) for a period of 72 hours. The data looked outstanding and terrifying at the same time – closed-loop control significantly improved time-in-target from 38% to 61% for the 100-180 mg/dl range (p<0.001). Mean glucose improved from 182 mg/dl to 161 mg/dl, just shy of statistical significance (p=0.065). The study used the Cambridge algorithm with unannounced meals, which made control much harder in the closed-loop arm. There was absolutely no difference in hypoglycemia (0% in both groups), and no severe hypoglycemia or adverse events were observed. We left the presentation reminded yet again of the very negative state of current inpatient glucose management. Indeed, we were downright disheartened by the standard of care overnight (mean glucose = 202 mg/dl), and the findings served as a striking reminder of: (i) the need for glucose management education in the hospital setting; and (ii) the great potential for inpatient technology to improve diabetes management and resulting outcomes. The tendency to accept hyperglycemia in inpatients is truly wrong, and we look forward to more studies of AID in this population.
  • This ADA featured less insulin-only vs. bihormonal debate than at ATTD 2016 or last year’s Scientific Sessions. The need for a stabilized glucagon with chronic exposure data has pushed the Bionic Pancreas’ bihormonal timing to 2019-2020. Dr. Ed Damiano, CEO of Beta Bionics, revealed that Zealand’s liquid stable glucagon analog will be tested in clinical trials with the fully integrated iLet bionic pancreas in 2H16. The pivotal studies of the insulin-only iLet are still expected to start in 2Q17, with an FDA submission planned for the end of 2017. The bihormonal pivotal trial, which will begin after the start of the insulin-only pivotal trial, will require that a subset of the study cohort use the iLet for 12 months in order to gain chronic glucagon exposure for a new indication for use of glucagon in a bihormonal bionic pancreas. That puts the bihormonal FDA submission timing into ~early 2019, putting potential approval around late 2019 or 2020.
    • Timing aside, glucagon does allow more patients to reach a mean glucose <154 mg/dl without increasing hypoglycemia. The Bionic Pancreas team again shared their fascinating insulin-only vs. bihormonal glycemic target studies, first discussed at ATTD. The randomized, crossover study (n=20) compared usual care to insulin-only and bihormonal versions of the Bionic Pancreas at different glycemic targets (insulin-only: 130 and 145 mg/dl; bihormonal: 100, 115, 130 mg/dl) over three-day experiments. The insulin-only and bihormonal systems were actually very similar with a glycemic target of 130 mg/dl: a mean glucose of 161 vs. 156 mg/dl and time <60 mg/dl of 0.8% vs. 0.5%. As the bihormonal target dropped to 115 and 110 mg/dl, mean glucose improved to 146 and 136 mg/dl without increasing hypoglycemia. The team is now exploring an insulin-only target of 110 mg/dl, as the use of 130 mg/dl was intentionally conservative.

Glucose Monitoring

  • ADA 2016 was a BIG meeting for sensor outcomes data: Dexcom’s DIaMonD study (testing CGM in MDI) and Abbott’s IMPACT study (testing FreeStyle Libre in well-controlled type 1s) both impressed. Both studies represented strong and positive results for Dexcom, Abbott and the entire field, and a signal of how far industry has come and where things are going in the future: proving outcomes.
    • Dexcom’s DIaMonD study randomized MDI users to six months of CGM (n=105) or six months of usual care (n=53). A1c declined a strong 0.9% with CGM at six months vs. -0.4% with usual care (baseline: 8.6%), for an adjusted mean difference of -0.6% in favor of CGM (p<0.001). The advantage for CGM was impressively consistent across age, baseline hypoglycemia, education, and diabetes numeracy – 60+ year-old CGM users saw the same benefit as 25-60 year-old users in this study. At the same time A1c declined, hypoglycemia significantly improved with CGM: a 30% improvement in time <70 mg/dl (-23 mins/day; p=0.006) and a strong 50% improvement in time <50 mg/dl (-11 mins per day; p=0.005), both outperforming 17% and 21% improvements with usual care (-15 mins, -6 mins). While the absolute reductions are not huge here, the high A1c baseline patients were not experiencing an overwhelming amount of hypoglycemia at baseline. On the high end, CGM users were spending 83 fewer minutes per day above range (>180 mg/dl) at 24 weeks, while the usual care group was spending nine more minutes per day above range (p=0.04). That translated to CGM users spending an hour more per day in range (70-180 mg/dl) at 24 weeks, while the usual care group spent 15 fewer minutes per day in range (p=0.006). CGM trended towards less severe hypoglycemia: a 2% rate (two out of 105 patients) vs. a 4% rate in usual care (two out of 53 patients). Glycemic variability also improved a bit with CGM (median CV: 42% to 38%), but did not change in usual care (42% to 42%) (p<0.001). Daily SMBG tests declined as expected in the CGM group (from 5.1/day to 3.6/day), but stayed roughly similar in the usual care group (5.1/day to 4.6/day) (p<0.001). CGM wear >6 days per week was seen in an impressive 89% of patients at six months, a testament to the better technology and the tight adherence criteria (>85% wear) patients had to demonstrate during the blinded CGM phase before randomization.
      • DIaMonD shows that MDI users not at glycemic target can definitely benefit from CGM – getting a meaningful reduction in A1c (-0.9% from baseline), shaving off highs, cutting their time in mild and dangerous hypoglycemia, and improving variability. We hope this large randomized study can help influence more CGM prescribing in MDIs, countering the “pump first” mentality that Dexcom has always battled. More importantly, we hope DIaMonD can influence professional guidelines and further improvement CGM reimbursement. DIaMonD is also a milestone for Dexcom, who has never run an outcomes study, and will need to do more to keep up with Medtronic’s and Abbott’s growing lists. Phase 2 of the study will cross some of the MDI patients over to pumps, so we’ll eventually see if insulin delivery method makes a difference. We want to see tools driving therapeutic change and creating “higher quality” A1cs and this certainly seemed to happen here.
    • Abbott’s IMPACT study compared FreeStyle Libre to SMBG in type 1 patients in very good control (baseline A1c: 6.7 %). The study met its primary endpoint at six months – relative to the control group, patients using FreeStyle Libre spent a striking ~74 minutes fewer per day <70 mg/dl (a 38% reduction; p<0.001). Pre-specified secondary endpoints were particularly compelling – patients using Libre spent ~49 minutes fewer per day <55 mg/dl (a 50% reduction; p<0.0001) and ~33 minutes fewer per day <45 mg/dl (a 60% reduction; p<0.0001). Measures of nocturnal hypoglycemia were also significantly lower with FreeStyle Libre as patients spent ~28 minutes fewer per night (a 40% reduction; p<0.0001) in hypoglycemia. Patients using Libre spent ~22 minutes fewer per day in extreme hyperglycemia > 240 mg/dl (p=0.02) and spent ~60 minutes greater/day between 70-180 mg/dl (p=0.0006). There was not a significant difference in A1c between the groups, and both saw a marginal ~0.15% increase by the end of the study – a positive given that these patients were spending three hours per day in hypoglycemia at baseline! In other words, FreeStyle Libre prompted a higher quality A1c, with one hour less hypoglycemia per day. The factory-calibrated sensor pretty much completely replaced fingerstick testing, suggesting a high level of confidence in its accuracy: SMBG frequency with FreeStyle Libre fell from a mean of ~5.5 tests/day at baseline to 0.5 tests/day (one every two days) at six months, a testament to the real-world accuracy in patients on insulin therapy. This is very good news as it seeks FDA approval, with now two large RCTs (REPLACE at ATTD and now IMPACT) backing up this finding.
      • IMPACT highlights the truly scary amount of hypoglycemia type 1s on insulin therapy are experiencing every day, and the tremendous challenges of dosing insulin as A1c approaches goal – all patients at baseline were spending ~200 minutes per day <70 mg/dl!!! The hypoglycemia data discussed above is very clinically meaningful (-74 minutes per day), and there is still room to improve therapeutic approaches: patients on Libre were still spending two hours <70 mg/dl per day at six months. Was the residual hypoglycemia driven by over-treating hyperglycemia while on FreeStyle Libre (so-called “hyper avoidance” in intensively managed patients)? Could that be managed with better education? Meanwhile, standard of care patients were still spending over three hours <70 mg/dl per day, no big change from baseline. In that sense, the results tell us as much about FreeStyle Libre’s ability to reduce hypoglycemia as they do about the real-world dangers of insulin therapy, especially in “well controlled” patients skating close to the edge; three hours per day in hypoglycemia is downright dangerous, at the same time these patients would be congratulated for getting below 7%. Avoiding lows on insulin therapy is truly difficult as A1c gets below 7%, and we’re not sure that delicate balance is appreciated enough. Libre and other sensors can help quantify that, and we hope clinical decision support software will help HCPs and patients start to titrate insulin in a data-driven way.
  • Where are glucose sensors going? Accuracy and reliability remain absolutely necessary, but they are no longer sufficient in this cost competitive, outcomes-driven, increasingly digital healthcare environment. It was just three years ago that ADA 2013 featured an entire oral session devoted to CGM accuracy and reliability. With multiple companies boasting available or upcoming sensors with MARDs of ~9-12%, the entire field has clearly picked up its game. Now, accuracy and reliability are the minimum criteria for any new sensor, as there is much more to consider: cost; clinical outcomes data to drive reimbursement; fingerstick calibrations; on-body size; prescribing hassle; connectivity, mobile apps, and clinical decision support software; etc. There is still tremendous room to expand the market, but the race is on to offer the most cost-effective and clinically impactful sensor system and to convince payers and patients of the added value. What will payers think of Dexcom’s DiaMond and Abbott’s REPLACE/IMPACT studies? Will they see this technology as very positive return-on-investment and standard-of-care therapy in type 1 diabetes? Will they make it less of a hassle to get on CGM, even in the US (e.g., no more prior authorizations, appeals, documentation)? Will outcomes and healtheconomic studies be the key frontier on which sensor battles are fought?
    • Automated insulin delivery will be a net positive for the CGM field, though with strong standalone sensor outcomes, will payers do a double take? “Wait, do we really need to cover an automated insulin delivery system (pump and CGM) if patients can get good outcomes with a sensor on MDI?” In that sense, do IMPACT and DIaMonD represent a threat to automated insulin delivery reimbursement? It’s hard to know, but these studies put some pressure on AID systems to show an additional, incremental advantage over best-in-class standalone sensors – particularly because improved apps, pattern recognition, and decision support software are going to make standalone sensors much better.
  • Will the FDA approve a non-adjunctive (BGM replacement) claim for CGM? Dexcom gave a persuasive preview of what we might expect at the July 21 FDA meeting. In short, the risk of an insulin overdose with Dexcom CGM was very low (~0-3%) based on the frequency of erroneously reading 20% or more above YSI in its pivotal trials. The retrospective risk analysis analyzed the two accuracy trials of the G4 Platinum + Software 505 (the same algorithm as in G5) in patients 2-17 years old (n=79) and 18+ years (n=51) vs. YSI. Dr. Walker concluded that G5 mobile is safe for diabetes decision-making, the risk for overdosing is likely minimal, and alerts and alarms further reduce the risk associated with non-adjunctive use of CGM. By contrast, patients using BGM for decision making get point in time snapshots, with no reference to direction, rate of change, or alerts and alarms, plus numerous interfering substances (not to mention hand washing and questionable meter accuracy in the post competitive bidding era). We thought it was a persuasive presentation and look forward to the full case Dexcom presents in a few weeks. Insulin dosing isn’t included on any BGM label, and we wonder how the FDA will approach that irony on July 21.

Data and Digital Health

  • The International Diabetes Center signed agreements to license its one-page, standardized Ambulatory Glucose Profile (AGP) report to Roche, Abbott, Diasend, and Glooko. This news marks an important step towards device-agnostic BGM/CGM download report standardization, which should improve clinical efficiency, hopefully drive less overwhelm and greater therapeutic change, and perhaps even expand adoption of CGM. Dr. Rich Bergenstal told us three other device companies and aggregators are expected to sign similar agreements in “the next month” – the big glucose monitoring players that have not signed on yet include Ascensia, Dexcom, J&J/LifeScan, and Medtronic. Ultimately, the vision for AGP is to become the EKG report of glucose data – something every clinician understands how to interpret and use – and we hope this creates momentum and pressure for every device company to sign on. Not every company is going to get what they want with a standardized report, but the field will benefit significantly from consensus, and companies can obviously innovate on top of AGP. This has been a long time in the making, as the IDC/Helmsley Charitable Trust expert panel on this topic convened in 2012, and the follow-up joint publication appeared in DT&T/JDST in 2013. Kudos to IDC, the Helmsley Charitable Trust, and so many advocates for pushing this forward, and we cannot to see how AGP is implemented and what impact it has on the field.
    • The partnerships give the companies the right to use the AGP in all their diabetes devices and existing software; the agreement with Abbott extends the groups’ existing partnership to other devices, since AGP is already used to visualize downloaded FreeStyle Libre glucose data. The Glooko agreement to use AGP will presumably allow Medtronic and Dexcom CGM data to be displayed in the one-page standardized format, though we wonder if both players will formally sign on. Presumably this expansion also means Roche’s CGM may use AGP when it launches.
  • Medtronic was extremely active on the diabetes data front at ADA, announcing summer updates to CareLink to help optimize pump settings, summer launches of the Glooko and IBM Watson partnerships, and a new food app partnership with Nutrino. It’s such a far cry from the siloed, proprietary Medtronic of three years ago, who simply did not partner and share data, and did not have a pipeline of mobile apps.
    • Next-gen CareLink Pro reports to optimize basal and bolus settings: These will launch this summer and identify optimal insulin:carb ratio, insulin sensitivity factor, and basal rate change. CareLink will suggest which time of day and direction pump settings should change (Increase basal rate from 8am – 12pm). These are step short of the exact recommendations DreaMed will provide with Glooko (“change basal rate to 0.75 u/hr from 8am-12 pm”), but a clear improvement over the status quo!
    • Glooko compatibility: Medtronic pump/CGM devices will (finally!) be compatible with Glooko’s web-based software, kiosk, and mobile app in July. This integration has been more than a year in the making (Medtronic invested in Glooko last March) and we give HUGE kudos to Glooko (and particularly Holly McGarraugh) for breaking open the Medtronic CareLink data silo.
    • Medtronic/IBM Watson Health app, SugarWise: The app is officially named “SugarWise (bringing insight to blood sugars) and is still expected to launch this summer. The first generation app will analyze retrospective data and provide insights based on past CGM, insulin, and nutrition data. The retrospective example from the pre-ADA Analyst Meeting said, “In the last 30 days, high glucose pattern found usually after glazed donut for breakfast.” A future-generation version will add the hypoglycemia prediction feature that we first saw at CES in January – unfortunate this won’t be in gen one.
    • Nutrino food app: The beta app launched during ADA for customers who use MiniMed Connect, providing an individualized picture of how daily food intake and other measures impact glucose levels – see the video here and download the app here. The app reads from Apple’s HealthKit, meaning it should work with Dexcom CGM and Bluetooth meters too (we have not fully tested it yet).
  • Abbott also had several key digital health announcements related to FreeStyle Libre at ADA, continuing the entire field’s move into connectivity, apps, and cloud-based software: (i) its LibreLink Android app for scanning FreeStyle Libre sensors has officially launched in Sweden and the Netherlands on Google Play and more countries are coming by end of month; (ii) a new integration agreement with Diasend enables data from the LibreLink app to automatically populate a patient’s diasend account wirelessly and passively ; and (iii) LibreView was unveiled in the exhibit hall, Abbott’s cloud-based data management software. It is excellent to see Abbott, Dexcom (G5), and Medtronic (MiniMed Connect) all offering mobile app data viewing and passive download to the cloud – now, we hope the magic of really driving therapeutic change with smart algorithms can begin! Abbott’s LibreLink is the only one of the three apps to offer direct Android compatibility for the patient, as both MiniMed Connect and G5 only work with a patient’s Apple iOS device. (Both allow followers to use Android, and both plan to launch Android patient apps this year).
  • In addition to the Medtronic progress, IBM Watson announced three more (!) diabetes partnerships with: (i) ADA to create a sophisticated diabetes advisor to help inform treatment decisions; (ii) HelpAround to provide crowd-sourced, on-demand help to people with diabetes who need it; and (iii) a predictive model to predict retinopathy risk with Israeli HMO Maccabi Healthcare. These augment the Medtronic Diabetes work (see above) and the Novo Nordisk partnership signed last December. With all these partnerships, Watson brings tremendous potential to improve prescribing, to personalize therapy, to improve prediction, and to make sense of all the data that already exists.
    • ADA: ADA CEO Mr. Kevin Hagan announced an exciting long-term partnership with IBM Watson to create a sophisticated diabetes advisor to help inform treatment decisions, plus potential apps for patients and researchers. Clinical decision support and more personalized therapy are clear goals – we can imagine a “Dr. Watson Advisor” that tells clinicians at the point-of-care what therapy to prescribe for a given patient at a given time, similar to its compelling work in cancer – leveraging the entire history of diabetes clinical trials, a patient’s entire case history, and perhaps genomic and other data to give evidence-based, confidence-ranked recommendations. What clinician wouldn’t love that? A new Watson-based innovation program, “Challenge Diabetes,” is also pushing developers to propose apps that will improve the lives of people with diabetes or prediabetes; submissions begin this summer and finalists will be announced this fall. We are elated to see this partnership and wonder if something would be ready by ADA 2017!
    • HelpAround: HelpAround is a fascinating “mobile safety net for people with diabetes,” an app that allows patients and caregivers to ask questions and even find supplies from local patients in moments of need. The IBM Watson partnership will “analyze every help request in real-time, assess its sentiment and tone, and identify frustrations, dissatisfaction and expressions of urgency,” helping further optimize the network of assistance. For example, recognizing in real-time that an individual is in distress in regards to their insulin or glucose levels will allow HelpAround to connect the patient with other insulin users, a nearby retailer, or even a chat with the insulin manufacturer.
    • Retinopathy: This Watson partnership with Israeli HMO Maccabi Healthcare will use machine learning to retrospectively sift through 20 years of data on two million patients to identify who is at risk of retinal damage. The information will be used to design personalized eye examination plans. Theoretically, this same paradigm could be applied to any number of diabetes complications in the future, so that they are caught and treated earlier in development. Nice!

Diabetes Drugs

Cardiovascular Outcomes Trials

  • While LEADER was arguably one of the more likely diabetes drug CVOTs to demonstrate cardioprotection, the results were nonetheless surprisingly positive (from a historical sense) and monumental – cardioprotection and renal protection announced simultaneously. There has been speculation about the potential for cardioprotection with GLP-1 agonists for some time due to the class’ positive effects on weight, blood pressure, and lipids and possible direct effects on the heart and vasculature. Novo Nordisk had expressed cautious optimism in several quarterly updates (most recently in 3Q15) that LEADER would be more likely than most CVOTs to reveal any benefit that existed due to its greater individual patient exposure compared to other trials (mandated minimum exposure of 3.5 years per patient and total exposure of over 30,000 patient-years). That said, there were also many reasons to expect a neutral outcome: the trial was only powered to show non-inferiority, it enrolled a high-risk patient population, any effect of GLP-1 agonists on CVD was expected to be subtle and gradual, and the only other GLP-1 agonist CVOT to report (ELIXA for Sanofi’s lixisenatide) had demonstrated neutral results. In that context, these results were certainly a pleasant surprise and a groundbreaking moment for the type 2 diabetes field.
  • The early consensus seems to be that the benefits in LEADER were most likely related to atherosclerosis. This was the main hypothesized mechanism of CV benefit for GLP-1 agonists before the results were released, as the class positively affects a number of endpoints related to atherosclerosis (e.g., glucose, blood pressure, weight) and may have direct effects on reducing arterial plaque. Speakers at the press briefing for LEADER and in the main results presentation agreed that the results appeared consistent with an atherosclerotic mechanism: the effects took some time to appear and increased over the course of the trial, and they were relatively consistent across multiple atherosclerotic endpoints. This is in marked contrast with the EMPA-REG OUTCOME results for Lilly/BI’s Jardiance (empagliflozin), which demonstrated an immediate effect on heart failure and CV mortality and little to no signal of an effect on MI or stroke. While we expect plenty of further speculation and investigation of the exact mechanism of benefit in LEADER (Dr. Laurie Baggio offered a few specific hypotheses in her discussant presentation), the field appears to be closer to a consensus hypothesis in this case compared to EMPA-REG OUTCOME.
  • We have many remaining questions about the clinical implications of the results that could take years to resolve. Dr. John Buse (University of North Carolina, Chapel Hill, NC) emphasized in his concluding presentation that the results should only be applied to the specific patient population enrolled in LEADER – those with longstanding type 2 diabetes and high CV risk. We expect that any updates to the Victoza label and to type 2 diabetes treatment guidelines will only be applied to this population in the absence of what would be a very expensive trial in a lower-risk population. However, we also imagine that many clinicians may incorporate the results into their risk/benefit calculus for Victoza even for lower-risk patients. We are also very curious to see what the implications will be for Saxenda (liraglutide 3.0 mg for obesity), which is unlikely to undergo a CVOT of its own. We would love to see Novo Nordisk conduct a CVOT for the more potent GLP-1 agonist semaglutide in patients with obesity and without type 2 diabetes, though we understand such a trial would also be very expensive. The question of a GLP-1 agonist class effect on CV outcomes is sure to be a hot topic for the next several years as CVOTs for other agents report results. In the near term, we expect the results to bolster the class as a whole but to disproportionately benefit Victoza until additional CVOTs report data. It will be very interesting to see how clinicians weigh the demonstrated CV benefits with Victoza against advantages like once weekly dosing with Lilly’s Trulicity (dulaglutide) or guaranteed adherence with Intarcia’s ITCA 650 (implantable exenatide mini-pump).
  • We are very curious to see how the LEADER and EMPA-REG OUTCOME results will be judged relative to each other. Will GLP-1 agonists and SGLT-2 inhibitors (or the specific agents in each class that have demonstrated CV benefit) both be considered preferred second-line treatments for all patients at high CV risk? Will the recommendations be different depending on the specific type of CV risk (i.e., empagliflozin for heart failure and liraglutide for atherosclerosis)? The prospect of combination therapy with two drugs that reduce CV risk by different mechanisms is also an intriguing one, though one attendee during a Tuesday session on EMPA-REG OUTCOME raised the possibility that the two mechanisms could actually work against each other if liraglutide reduces ketone body production that is contributing to the benefit with empagliflozin.
  • Large-scale changes to the FDA’s 2008 CV Guidance appear increasingly unlikely now that two CVOTs have reported positive results. The consensus opinion has certainly changed from a year ago, when the streak of four completely neutral trials (SAVOR, EXAMINE, TECOS, and ELIXA) had raised questions about whether the value of these trials was worth the massive investment. Now that two trials have revealed important benefits that might otherwise have remained unknown, we have heard several speakers (including Dr. Darren McGuire and Dr. Steve Nissen at AACE) argue strongly that the field is getting its money’s worth from these studies. Even some previous opponents of the FDA Guidance have changed their opinions over the past year – for example, Dr. Silvio Inzucchi (Yale University, New Haven, CT) stated at EASD that he was prepared to completely revise his previous assessment of the requirements in light of the EMPA-REG OUTCOME results. At the same time, the FDA officially eliminated the Risk Evaluation and Mitigation Strategy for rosiglitazone last December, effectively declaring the main rationale for the 2008 Guidance to be invalid. We also continue to question whether an across-the-board CVOT requirement with the same guidelines for all diabetes drugs is the most effective tool to assess the risks and benefits of new products. We believe that a more nuanced approach, in which drugs with a signal for CV risk would be required to conduct a safety trial and those with potential for benefit would be required or incentivized to conduct a superiority trial, would offer the most value to the field.
  • An intriguing new “fuel energetics” hypothesis for the mechanism of benefit in EMPA-REG OUTCOME generated plenty of discussion at this year’s ADA. The thrust of this hypothesis, outlined in a paper published in Diabetes and a presentation by Dr. Ele Ferrannini (University of Pisa, Italy), is that the shift toward ketone body production with SGLT-2 inhibitors (which has been discussed primarily in the context of increased risk of ketoacidosis) might have cardioprotective effects. In his model, the increased availability of lipid substrates with SGLT-2 inhibitors (due to increased glucagon production and decreased insulin and glucose levels) leads the liver to produce more ketone bodies, which are then taken up by the heart and act as very efficient fuel sources. The increased hematocrit (higher ratio of oxygen-carrying red blood cells to total blood volume) seen with SGLT-2 inhibitors could also lead to more oxygen being delivered to the heart. That combination of more oxygen and more efficient energy utilization could improve the heart’s contractile ability and lessen the strain on a failing heart. A separate paper and presentation by Dr. Sunder Mudaliar (UCSD, San Diego, CA) suggested that a similar hypothesis could apply to the renal protective effects seen in the trial. The basic idea is that a shift by the kidneys toward metabolism of ketone bodies rather than oxygen could help ameliorate renal hypoxia and oxidative stress, which are increasingly being recognized as key contributors to the progression of chronic kidney disease. While these hypotheses do not preclude other previously proposed mechanisms of benefit, the level of attention they received throughout the conference suggests that they will be an important part of the discussion moving forward.
    • If this hypothesis is correct, we look for the field to weigh the beneficial long-term effects of increased ketogenesis on cardiovascular/renal outcomes against the short-term increased risk of DKA. The risk/benefit assessment will likely vary depending on the patient population. Based on current evidence, it seems likely that the benefits will clearly outweigh the risks for patients with longstanding type 2 diabetes and high CV risk, as the EMPA-REG OUTCOME results are most directly applicable to this population and demonstrated no increased risk of DKA. The calculus is somewhat less clear for the broader type 2 diabetes population, but it still seems likely that the benefits will outweigh the risks given that the rates of SGLT-2 inhibitor-associated DKA in type 2 diabetes appear to be low and associated with specific precipitating factors – see our coverage of last fall’s AACE/ACE meeting on the subject for more. The situation may be trickiest in type 1 diabetes, where the risk of DKA appears to be more marked and there is unlikely to be a long-term outcomes trial to evaluate potential cardiovascular and renal benefits. Of course, much more study is needed before making any definitive statements about these tradeoffs, but there is certainly potential for clinicians to face a bit of a paradox.
  • A hypothesis-generating mediation analysis of the EMPA-REG OUTCOME results suggested that changes in hematocrit levels (presumably due to a reduction in plasma volume) could partially account for the 38% risk reduction for cardiovascular death. The covariate mediation analysis examined a host of potential factors to see if they could account for the impressive effect on cardiovascular mortality. Potential mediators were related to glycemia (A1c, fasting plasma glucose [FPG]), vascular tone (systolic blood pressure, diastolic blood pressure, heart rate), lipids (HDL cholesterol, LDL cholesterol, triglycerides), renal factors (log urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate [eGFR]), adiposity (weight, BMI, waist circumference), volume status (hematocrit), or other (uric acid). A “change from baseline” analysis meant to determine a potential acute effect suggested that hematocrit levels and a decrease in plasma volume could explain nearly 52% of the overall effect of empagliflozin on cardiovascular death. An “updated mean” analysis meant to tease out chronic effects similarly found that hematocrit levels could account for 52% of the effect, while other volume-related factors such as hemoglobin and albumin levels could explain nearly 46% and 32% of the effect, respectively. While this interesting post-hoc analysis suggests a role for plasma volume in the cardioprotective benefit of empagliflozin, presenter Dr. Silvio Inzucchi (Yale University, New Haven, CT) emphasized that the analysis suggests that the plasma volume is only a partial mediator of the effect and other potential drivers (like ketone bodies) may not have been included in the analysis because they were not adequately measured at baseline and throughout the study
  • Additionally, we heard speakers use the growing pool of CVOT data in discussions on various safety signals, including heart failure and bone health. Specifically, Dr. Steven Marso (UT Southwestern, Dallas, TX) presented on the anti-glycemic therapies on heart failure risk, pulling from the CVOTs of DPP-4 and SGLT-2 inhibitors in efforts to draw conclusions on each drug class’s risk. Dr. John Buse (University of North Carolina, Chapel Hill, NC) also examined the effects of diabetes drugs on bone health, as he turned to CVOTs in GLP-1 agonists, DPP-4 inhibitors, and SGLT-2 inhibitors to identify the levels of risk. Notably, Dr. Buse supported the use of CVOT data over the meta-analysis of smaller studies for regulatory or clinical decisions. While the field’s conclusions on these safety signals remain limited, we would agree that the growing evidence base from CVOTs and their hard endpoints have helped contribute important insights on our available diabetes drugs, outside of only cardiovascular disease.
  • The fact that there are now two diabetes drugs with demonstrated renal protective effects is one of our most exciting and surprising conclusions from ADA 2016. Full renal outcomes results from EMPA-REG OUTCOME presented by Dr. Christoph Wanner and published in the NEJM demonstrated a significant 39% risk reduction for incident or worsening nephropathy with Lilly/BI’s Jardiance (empagliflozin) (HR = 0.61; 95% CI: 0.53-0.70; p<0.001). In addition, one of the most positive surprises from the LEADER results was the significant 22% improvement in renal outcomes (HR = 0.78; 95% CI: 0.67-0.92; p=0.003) with Novo Nordisk’s Victoza (liraglutide). These findings are truly profound given the current enormous unmet need for new therapies to treat chronic disease. We hope they might prompt both sponsors to consider conducting a dedicated chronic kidney disease trial for their products, comparable to Lilly/BI’s planned heart failure trials for Jardiance. We also wonder what the implications will be for ongoing and future trials of drugs being developed specifically for diabetic nephropathy – will those agents be required to demonstrate a benefit in addition to that provided by Victoza and/or Jardiance?
    • The FDA’s recent Drug Safety Communication about the risk of acute kidney injury with J&J’s Invokana (canagliflozin) and AZ’s Farxiga (dapagliflozin) could potentially complicate the discussion around the renal effects of SGLT-2 inhibitors. The warning was based on a search of the FDA Adverse Event Reporting System that found 101 confirmable cases of acute kidney injury with the two drugs between March 2013 and October 2015. Jardiance was not mentioned in the warning, and there was no signal of increased risk of acute kidney injury with Jardiance in EMPA-REG OUTCOME. This discrepancy suggests that there could be within-class differences in the effect of SGLT-2 inhibitors on the kidneys, which would be surprising given how homogenous the class is typically considered to be. Results from the ongoing outcomes trials for Invokana and Farxiga should help clarify this question; there could potentially be difficult tradeoffs for clinicians if those trials find both an increased risk of acute kidney injury and a reduced risk of long-term cardiovascular and/or renal risk with these drugs. It is too early to reach any definitive conclusions but we will be keeping a close eye on this area.

Updates on New and “New” Insulins

  • New rapid-acting insulin analogs stepped into the spotlight at ADA 2016, following several years in which basal insulins stole the show. Innovation in the rapid-acting insulin analog field has occurred at a somewhat slower pace compared to the basal insulin field that recently saw the US launches of next-generation options from Sanofi (Toujeo [U300 insulin glargine]) and Novo Nordisk (Tresiba [insulin degludec]). Like Toujeo and Tresiba, the next-generation rapid-acting insulin analogs seem to offer meaningful but incremental benefits over existing products but are not expected to be paradigm-shifting innovations. Many of the most notable rapid-acting insulins are variations on existing insulins, rather than entirely new molecules. The data we’ve seen thus far suggest that the new products offer significant but modest improvements in postprandial glucose control, are non-inferior or very modestly superior in terms of A1c reduction, and produce comparable or slightly improved hypoglycemia rates compared to current rapid-acting analogs. Perhaps most excitingly, it appears that the next-generation products may retain their efficacy with mealtime or even post-mealtime dosing, as opposed to the 15 minutes pre-mealtime dosing recommended with the current rapid-acting insulins. This potential for greater dosing flexibility should be very meaningful for patients, as it is more consistent with how many patients dose mealtime insulin in the “real world.” 
    • The most advanced next-generation insulin analog is Novo Nordisk’s faster-acting insulin aspart, which presented full phase 3 Onset 1, Onset 2, and Onset 3 data at ADA 2016. Onset 3 found that intensification to a basal-bolus regimen with faster-acting aspart in patients with type 2 diabetes resulted in a statistically superior mean A1c reduction of 0.94% (baseline A1c=7.9%; p<0.0001) compared to continued treatment with basal insulin alone. In a head-to-head comparison, Onset 2 found that faster-acting insulin aspart administration in patients with type 2 diabetes produced non-inferior A1c reductions and significant improvements in postprandial control compared to Novo Nordisk’s NovoLog (insulin aspart). A1c dropped from 8% to 6.6% with faster aspart and from 7.9% to 6.6% with NovoLog. Faster aspart produced a significant 10.6 mg/dl improvement in one-hour postprandial glucose (p=0.0198) and a numerical but not significant improvement of 6.6 mg/dl in two-hour postprandial glucose. In patients with type 1 diabetes, Onset 1 found a modest but statistically significant improvement in A1c with Faster aspart (~0.2% vs. standard aspart). Notably, in addition to the modest A1c benefits, two-hour postprandial blood glucose levels were superior with Faster aspart than regular aspart (by ~12 mg/dl), and, in terms of A1c reduction, post-meal Faster aspart administration was non-inferior compared to standard pre-meal administration of current insulin aspart.
    • Adocia offered a glimpse at phase 1b meal study results for its Lilly-partnered BioChaperone Lispro and its BioChaperone Combo (insulin glargine/insulin lispro). Both demonstrated improvements in one-hour and two-hour postprandial glucose compared to Lilly’s Humalog (insulin lispro). BioChaperone Lispro demonstrated a mean glucose difference of 42 mg/dl one hour post-meal and a mean difference of 27 mg/dl two hours post-meal. BioChaperone Combo reduced postprandial glucose excursions by 24 mg/dl at one hour compared to Humalog. BioChaperone Combo produced numerically fewer hypoglycemic episodes compared to Humalog and was associated with more time in range. Hypoglycemia was comparable between BioChaperone Lispro and Humalog.
    • MannKind’s Afrezza (inhaled insulin) also demonstrated improvements compared to Lilly’s Humalog (insulin lispro) in terms of a faster onset and shorter duration of action. Afrezza is one of the few new rapid-acting insulins that arguably represents a true, groundbreaking innovation, given its unique delivery method. Unfortunately, burdensome prescribing requirements and potential safety concerns related to the novelty of the product have led to sluggish uptake for Afrezza in the year and a half since its launch. The product has been further plagued by Sanofi’s decision to terminate its licensing agreement with MannKind for Afrezza and MannKind’s CEO woes in the early half of this year. That said, many patients on Afrezza extoll its benefits and we believe that the hurdles presented by the prescribing requirements and other concerns can be mitigated. MannKind appears committed to keeping Afrezza available and announced during ADA that it intends to partner with JDRF to investigate Afrezza for a pediatric population.
  • There’s new and then there’s “new” insulins – we saw results from phase 3 trials of Merck/Samsung’s biosimilar insulin glargine MK-1293 and Sanofi’s biosimilar insulin lispro SAR342434 for the first time. In an oral and a poster presentation, MK-1293 demonstrated similar efficacy and safety to Sanofi’s Lantus (insulin glargine) in both patients with type 1 and type 2 diabetes over 24 weeks. Merck recently shared that it has filed MK-1293 in Europe and we presume a US filing will follow soon. MK-1293 will likely be the second biosimilar insulin glargine to market, after Lilly/BI’s Basaglar/Abasaglar that has already launched in multiple ex-US markets and will launch in the US in December 2016. Biocon/Mylan also have a biosimilar insulin glargine in the works that they hope to file in the US and EU in the next few months. On the rapid-acting insulin side, Sanofi’s biosimilar insulin lispro SAR342434 demonstrated similar effects on A1c and postprandial glucose excursions with a similar safety profile as Lilly’s Humalog (insulin lispro) in combination with Sanofi’s Lantus (insulin glargine) in patients with type 1 diabetes.
  • The basal insulin front was comparatively quiet at this year’s ADA. Most notably, in a series of late-breaking posters, we saw full SWITCH 1 and SWITCH 2 results demonstrating a hypoglycemia benefit for Novo Nordisk’s Tresiba (insulin degludec) over Sanofi’s Lantus (insulin glargine). Novo Nordisk plans to submit this data to the FDA soon, in the hopes that it will support some sort of language surrounding reduced risk of hypoglycemia in Tresiba’s label.

GLP-1 Agonists

  • Data presented at this year’s ADA illustrated a number of exciting potential future directions for the GLP-1 agonist class – the question is whether there will be a market for all of them. We expect that the demonstration of a cardioprotective effect for Novo Nordisk’s Victoza (liraglutide) in LEADER will likely spur growth of the entire class and provide some disproportionate benefit for Victoza. Over the long term, it is possible that some clinicians will use CVOT results as a key differentiating factor when choosing among different agents in the class, at least for their higher-risk patients. This will likely depend in large part on the consistency of results from future GLP-1 agonist CVOTs. Combinations with basal insulin represent another exciting advance for the GLP-1 agonist class; at this year’s ADA, we saw full phase 3 results for Sanofi’s iGlarLixi (lixisenatide/insulin glargine) combination, which is expected to receive US and EU regulatory decisions this year. Novo Nordisk’s Xultophy (insulin degludec/liraglutide) is also on track for a US decision this year and is already available in Europe. Impressive new data for Novo Nordisk’s semaglutide (in type 2 diabetes and obesity) reinforced its potential as a versatile, possibly best-in-class molecule, while results from the FREEDOM-2 trial of Intarcia’s ITCA 650 (implantable exenatide mini-pump) underscored the advantages of an agent that offers guaranteed adherence. We are excited about the potential for all of these products to help expand usage of the GLP-1 agonist class in both type 2 diabetes and obesity, which we have long felt is underutilized. It is not clear at this point whether all the options can find their own niche within the class or whether one or two will emerge as the clear preferred options.

SGLT-2 Inhibitors in Type 1 Diabetes

  • A session on novel therapeutics for type 1 diabetes underscored the continued interest in the use of SGLT-2 inhibitors in type 1 diabetes. In particular, we saw glycemic variability data from J&J’s phase 2 trial of Invokana (canagliflozin) in patients with type 1 diabetes. In the CGM substudy, MAGE (a measure of glucose variability) was 17 mg/dl improved over placebo with canagliflozin 100 mg and 38 mg/dl improved over placebo with canagliflozin 300 mg. As assessed by CGM, time in range (70-180 mg/dl) improved by roughly 14% placebo-adjusted, driven entirely by a reduction in hyperglycemia, with no major increase in hypoglycemia. This was some of the most compelling data we’ve seen on SGLT-2 inhibitors’ benefits on time-in-range and glycemic variability to date. Similarly, another presentation demonstrated markedly less chaotic CGM tracings with the addition of dapagliflozin (AZ’s Farxiga) to a regimen of GLP-1 agonist liraglutide and insulin in patients with type 1 diabetes.
  • A major theme at the annual TCOYD/The diaTribe Foundation forum was the need for better therapies for type 1 diabetes. In particular, Dr. Jeremy Pettus (UCSD, CA) spoke movingly about his own challenges managing his blood sugars while at ADA, despite the fact that he is well-educated, has health insurance, and has access to all of the best diabetes management tools. Regarding SGLT-2 inhibitors specifically, Dr. Pettus stated, “When I have a patient with type 1 diabetes who takes the drug, they say, ‘My life is better. Maybe I should’ve bolused four units and only bolused for three, and the SGLT-2 inhibitor picks up the slack. It takes away some of the chaos.’ That’s the real value of some of these medications.”

The Future of Type 2 Diabetes Drugs

  • It is becoming increasingly clear that future type 2 diabetes drugs will need to offer additional benefits beyond glucose lowering to be successful. We can even imagine a future in which new type 2 diabetes drugs will have to demonstrate a positive effect on cardiovascular and/or renal outcomes in order to succeed now that two agents in different classes have already done so. We are also encouraged to see interest in evaluating such benefits with older generic drugs like pioglitazone in the IRIS trial and metformin in the planned GLINT trial. Demonstrating benefit in additional indications like obesity, type 1 diabetes, and NASH is potentially another way for type 2 diabetes drug manufacturers to differentiate their products. We saw results of several such efforts at this year’s ADA, including data on semaglutide, exenatide/dapagliflozin, and canagliflozin/phentermine in obesity and data on canagliflozin and dapagliflozin in type 1 diabetes. New drug classes like the GLP-1/glucagon dual agonist class promise benefits on weight and other cardiovascular risk factors in addition to reductions in glucose. The bottom line is that we see little room in the current landscape for new drugs that offer nothing more than incremental glucose-lowering benefits, or those (other than insulin) that carry a risk of weight gain or hypoglycemia.
  • We saw a substantial amount of promising new data on GLP-1/glucagon dual agonists in type 2 diabetes and obesity at ADA 2016. Most notably, we saw expanded phase 1 data for Sanofi’s SAR425899, demonstrating significant reductions in weight, “clear” improvements in A1c and fasting plasma glucose, and a similar safety/tolerability profile as GLP-1 single agonists. A phase 1, randomized, blinded study of AstraZeneca’s MEDI0382 GLP-1/glucagon receptor dual agonist found that the candidate was well tolerated overall, with reduced postprandial glucose levels and daily food intake at doses of 5, 10, 30, 100, 150, and 300 micrograms. Further, a preclinical study demonstrated that a single subcutaneous dose of MEDI0382 reduced fasting glucose levels by 42%, glucose AUC by 53%, and food intake by 18% in wild type but not GLP-1 receptor KO mice. We were also interested in a poster presentation of new data on the cholesterol-lowering effect of Janssen/Hanmi’s phase 1 dual agonist HM12525A. As a class, GLP-1/glucagon dual agonists have generated some of the most buzz and industry investment out of any classes in the early-stage diabetes drug pipeline. Much of the recent Keystone Symposia on Novel Therapeutics for Diabetes and Obesity focused on this class and other polyagonists involving GLP-1 agonists. The promise of a winning combination of glucose-lowering, weight reduction, and even potentially cardioprotection has led several pharmaceutical companies to add these candidates to their early-stage pipelines – see our competitive landscape for more.
  • We heard several key diabetes clinical care experts speak to the importance of treating the right patients with the right medications at the right time. During the 10th annual TCOYD/The diaTribe Foundation Diabetes Forum, Drs. Steve Edelman (UCSD, San Diego, CA), Rury Holman (University of Oxford, UK), Anne Peters (USC, Los Angeles, CA), Jeremy Pettus (UCSD, San Diego, CA), and John Anderson (The Frist Clinic, Nashville, TN) spoke eloquently on the need to improve access and adherence to maximize the efficacy of currently available diabetes drugs. As Dr. Edelman put it, “One of the biggest challenges is getting the right drug to the right person. The second big part is getting people to be adherent and persistent and make diabetes higher on their priority list.” Dr. Holman suggested that part of the problem is that clinicians don’t have all of the information they need to offer truly personalized, tailored therapeutic options to their patients. He suggested enriching the clinical trial process so that trials yield more information useful for personalized therapeutic recommendations. During the ADA meeting itself, the highly respected Dr. Judith Fradkin offered an update on the NIH’s plans for rolling out its Precision Medicine Initiative (PMI) Cohort Program and noted that diabetes will be one of the most highly represented conditions in the cohort, with an estimated 135,658 cases at baseline.

Additional Topics

Obesity

  • There was no major new obesity data this year and we saw very little representation from branded obesity pharmacotherapies this year. Aside from Novo Nordisk’s relatively minimalist booth on Saxenda (liraglutide 3.0 mg), no other obesity companies were represented on the exhibit hall floor. In addition, there was only one obesity-focused corporate symposium (supported by Novo Nordisk) on the agenda. The level of engagement from obesity drug companies has been on a sharp decline over recent ADA meetings, as 2014 featured large, bustling booths from Belviq (lorcaserin) and Qsymia (phentermine/topiramate extended-release) and 2015 had Saxenda, but only a small pop-up booth for Belviq. We are not surprised by this drop-off in marketing, given the recent challenges in the obesity drug market, although we remain hopeful that Novo Nordisk’s wealth of expertise and resources will push for greater awareness and education around obesity to gradually boost the market.
  • Notably, we saw a significant amount of promising new data on type 2 diabetes drugs in obesity management. Combination therapies, SGLT-2 inhibitors, and GLP-1 agonists were the stars of this show, headlined by phase 2 results of combination therapy with AZ’s Farxiga (dapagliflozin) and Bydureon (exenatide once weekly), which demonstrated significant ~4 kg weight loss vs. placebo in patients with obesity but not diabetes. In addition, co-administration of J&J’s Invokana (canagliflozin) and phentermine showed significantly greater weight loss vs. placebo in adults with overweight and obesity. On the GLP-1 agonist front, we saw positive results on reductions in energy intake and appetite with once-weekly GLP-1 agonist semaglutide in obesity as well as significant weight benefits from the FREEDOM-2 study of Intarcia’s ITCA 650 (implantable exenatide mini-pump) compared to Merck’s Januvia (sitagliptin) in people with type 2 diabetes. While data from currently available obesity drugs and new targets remained on the quieter side at this meeting, we were glad to see many diabetes drugs turn to this area and given the complexity of obesity, we are also pleased to see more focus on combination therapies. With the diabetes drug space having comparatively greater resources, a larger evidence pool, and established efficacy and safety, we hope to see greater movement from this market into obesity, as the disease remains a significant unmet need.
  • On the basic science front, the brain and microbiome seemed to be the main focuses within obesity research. The agenda featured several intriguing oral presentations on deep transcranial magnetic stimulation, AgRP neuronal activation, and a leptin-responsive brainstem circuit within weight management. As we’ve seen recently, GLP-1 agonists have been heavily studied in this area, as highlighted by an oral presentation examining the regulation of energy balance and glucose homeostasis via the ventromedial hypothalamic GLP-1 receptor. See our recent coverage from the European Obesity Summit for greater discussion on how the brain plays a significant role within energy balance and weight management. Additionally, we heard a decent number of presentations on how the microbiome ties into obesity, with discussions on the interaction between “diabesity” genes and the gut as well as a full symposium on how the microbiome is involved in metabolic risk from pregnancy through the life cycle. While these presentations highlight promising movement, we are increasingly aware of the complexity of both obesity and the corresponding therapies. Of the brain and microbiome, we see the brain and its neural circuitry as a more near-term target area for obesity, although we ultimately hope to see multi-targeted therapies combining these many different approaches.
  • In addition, the role of adipose tissue and its link to obesity and type 2 diabetes risk was in the spotlight at this year’s prestigious Banting lecture, delivered by Dr. Barbara Kahn (Harvard Medical School, Boston, MA). This area of research has certainly been growing rapidly within recent years, as Dr. Kahn noted our evolving understanding of adipocyte tissue as a storage depot to its role in secreting molecules. Dr. Kahn illustrated the complexity and potential of studying adipose tissue, as she touched on how the molecules, lipid levels, and biochemical changes involved in adipose tissue can guide our search for novel drug targets in obesity and type 2 diabetes. We especially enjoyed hearing how these approaches can be used to identify our most at-risk patients and help personalize prevention and treatment efforts. For more on our growing understanding of adipose tissue, also check out the prestigious Minkowski award lecture delivered by Dr. Matthias Bluher (University of Leipzig, Germany) at this past EASD.

The Limitations of A1c

  • ADA 2016 underscored the limitations of using A1c alone to titrate therapy: a mean glucose can range 80 mg/dl for a given A1c (8.0% =120 mg/dl or 200 mg/dl)! This was not groundbreaking by any means – we’ve long argued that A1c in isolation is not the best metric for glycemic control – but this meeting’s commentary went further, stressing that A1c is not simply inadequate, but can be dangerously misleading and clinically ignorant. Dr. Rich Bergenstal drove this point home during his presentation on racial differences in the relationship between mean glucose and A1c, sharing striking data that mean glucose can range 80 mg/dl for a given A1c – e.g., an estimated A1c of 8.0% could correspond to a mean glucose of 120 mg/dl or 200 mg/dl. That’s some serious dispersion between different individuals! Noted UW’s Dr. Irl Hirsch, “the paradigm by which we treat type 2 diabetes is wrong and we’ve been doing it wrong for the past 30 years” [e.g., treating a patient with mean glucose of 120 mg/dl and 200 mg/dl the same because the A1c reads 8.0%]. He and Dr. Bergenstal did acknowledge that A1c is an established measure of the risk of developing complications but highlighted that we would be wise to shift the existing paradigm and begin personalizing diabetes and treatment decisions based on glucose values. Especially in this era of pharmacotherapies and technologies that may improve quality of A1c – shaving off highs and lows, but not impacting A1c substantially – the commentary underscored the need for more widespread glucose monitoring and tools that capture “higher quality” A1cs. A big question, of course, is how to validate such a paradigm shift in the eyes of payers and the FDA. Will anyone fund a modern-day DCCT to validate the importance of time-in-range and reducing hypoglycemia and variability?
  • Abbott’s IMPACT study also highlighted just how much A1c completely obscures dangerous hypoglycemia. As a reminder, both groups in the study saw a non-significant, marginal 0.15% increase in A1c (6.7% to 6.9%), though the “quality of A1c” improved markedly in the FreeStyle Libre group – 74 fewer minutes per day <70 mg/dl (a 38% reduction), and 33 fewer minutes per day <45 mg/dl (a 60% reduction in time spent at a highly dangerous level). Meanwhile, the control group was still spending three hours per day in hypoglycemia with an A1c 6.9%! Do payers appreciate the gravity of that change? How could that change impact short and long-term costs? The results underscored that A1c and average glucose is not just an incomplete metric, but that glucose control for most patients is defined in terms of MANY other variables: hypoglycemia, hyperglycemia, time-in-range, variability, quality of life, fear, hospitalizations, etc.

Focus on the Cost of Diabetes and Inequity

  • The rising cost of diabetes care was heavily discussed at this year’s meeting, and we noticed particular attention to inequities among various patient populations. We were reminded throughout the conference that the US spends dramatically more on diabetes than any other country, with costs totaling $245 billion. As outlined by Dr. Neda Laiteerapong (University of Chicago, IL), the principle driver of this trend is rising medical costs, particularly for insulin expenditures. However, she also brought up the bright spot that overall rising diabetes costs may partially reflect the greater longevity and thus greater utilization of healthcare services of people with diabetes. On the same note, a presentation by Dr. Xilin Zhou (CDC, Atlanta, GA) highlighted tremendous growth in spending on anti-diabetes drugs in the US, with alarming statistics of a 12-fold increase in under two decades. Additionally, we heard discussions on the differences in out-of-pocket expenses (OOPEs) among patient populations. Specifically, Dr. Lina Merjaneh (Seattle Children’s Hospital, WA) highlighted that young adults with type 1 diabetes pay approximately six times more than those with type 2 diabetes. On a more hopeful note, Dr. David Howard (University of Nevada, Reno, NV) explained that OOPEs for vulnerable populations are actually on a downward trend, though this decreased spending may merely reflect the necessity of opting for cheaper, generic drugs. We were glad to see this more nuanced examination of costs at this year’s ADA, as this can help develop a more targeted strategy to tackle the unsustainable trends we’re seeing.
  • In addition, we were pleased to witness greater dialogue on how to treat diabetes in different populations. Drs. Richard Bergenstal (International Diabetes Center, St. Louis Park, MN) and Roy Beck (Jaeb Center for Health Research, Tampa, FL) discussed new findings to support racial differences in the relationship between mean glucose and A1c – an important topic, given how much we depend on A1c in our treatment approaches (see below). In addition, health equity researcher Dr. Nadia Islam (New York University, New York, NY) criticized the fact that the >30 Asian-American ethnic groups in the US are grouped uniformly as “Asian” in analyses of diabetes prevalence and management, despite the fact that these groups can be highly heterogeneous. Dr. Yvette Roubideaux (Washington State University, Spokane, WA) described a similar phenomenon in the American Indian and Alaska native communities, highlighting that the 566 federally-recognized tribes in the US requires a comparably diverse range of approaches to diabetes education and treatment. We also heard the first full results of the COSMID (Comparison of Surgery vs. Medicines for Indian Diabetes) trial, which was the first-ever RCT of surgical vs. non-surgical care for type 2 diabetes in South Asian patients. We hope that these findings can serve as an impetus for policymakers and diabetes researchers to be more attentive to the heterogeneity of the US patient population, with the development of more evidence-based guidelines on how to personalize treatment by this dimension.

What Is ADA’s Role?

  • During a compelling presidential address, ADA President Dr. Desmond Schatz (University of Florida, Gainesville, FL) issued a call to urgency, emphasizing the ADA’s focus on prevention through raising awareness of the scope and cost of diabetes. He underscored the need to bring diabetes to 212 degrees – “the boiling point of water where it erupts with urgency” – to transform the “invisible disease” to a highly visible crisis. Dr. Schatz detailed the many ways in which diabetes is invisible, hidden, and ignored: people hide the reality of living with diabetes from their friends and families, healthcare providers are largely absent in the daily management of the disease, and patients with type 2 diabetes often choose to be invisible due to stigma and feelings of failure. In addition, Dr. Schatz emphasized that although diabetes is far more prevalent, NIH funding for the disease pales in comparison to that for HIV/AIDS and cancer – an incredible $35 per patient for diabetes vs. $2,500 for HIV/AIDS and $372 for cancer, another byproduct of its invisibility. To that end, he advocated for taking a page out of the book of successful movements such as those for HIV/AIDS and even the recent Zika epidemic (which recently received a $1.1 billion compromise bill), where people have rallied around a strategic vision and inspired a “fiery sense of urgency”. We found Dr. Schatz’s presentation incredibly compelling, and are pleased to see the ADA call for immediacy and action in the diabetes world; perhaps through mimicking successful health advocacy movements, we can collectively “turn up the heat” and inspire the sense of urgency required to confront the diabetes epidemic. 
  • The ADA drew significant attention to its Pathway to Stop Diabetes program this year with a dedicated symposium, poster session, and oral presentation session. The closed Pathway symposium on the first day of the conference featured presentations from the latest round of grant recipients, while the oral presentation and poster sessions featured presentations from the 2014 and 2015 awardees. We have been impressed with the Pathway initiative since its inception in 2014; the program awards grants of up to $1.6 million over five to seven years to young diabetes researchers working on innovative projects focused on everything from neuronal regulation of feeding behavior to impaired wound healing. The program is supported by several heavy hitters in the diabetes industry, including Sanofi, Novo Nordisk, Lilly, and AstraZeneca, and we imagine this could make it easier for the researchers to eventually translate their findings into novel therapies. We think this program can play a major role in shaping the next generation of KOLs in diabetes. We also hope it can promote a more diverse group of leaders compared to the current crop (in a sign of some progress, 35% of the Pathway grant recipients thus far are women compared to 26% of the mentors).
    • Many of the featured presentations focused on the themes of the role of the microbiome, neural regulation of hunger, and the promise of genomic approaches to understand the biochemical signatures and gene regulatory networks underlying diabetes and obesity.

Precision Medicine Initiative

  • We were glad to see the progress on President Obama’s Precision Medicine Initiative (PMI) continue at ADA 2016. Most notably, the highly respected Dr. Judith Fradkin (NIDDK, Bethesda, MD) presented the NIH’s plans for rolling out the PMI Cohort Program, sharing ambitious benchmarks slated for completion by the end of 2016. The NIH aims to have 79,000 participants fully consented and enrolled in the cohort, with biospecimens from at least 25,000 participants; the Institute expects to accomplish its final goal of enrolling one million participants by the end of 2019. Further, the NIH plans to launch a direct volunteer program and partnerships with five to seven major healthcare provider organizations to facilitate participant recruitment, and also expects that eight to ten studies using the cohort data will be underway by December 2016. It is very encouraging to see the government’s commitment to developing a strategic plan for the PMI implementation – we hope to see the momentum continue and ultimately bring more accurate diagnoses, improved disease prevention strategies, and better treatment selection for people with diabetes and other chronic diseases.
  • Meanwhile, Dr. Jose Florez (Massachusetts General Hospital, Boston, MA) expressed concern that the field might not yet be ready to apply PMI findings in diabetes as there is still so little known about the genetic underpinnings of the disease. To that end, he highlighted the Accelerating Medicines Partnership Type 2 Diabetes Knowledge Portal, which will enable scientific advances through improved data collection, sharing, and analytics.

Exhibit Hall

  • The ADA 2016 exhibit hall seemed to have less fanfare, attendance, and excitement than we’ve seen in the past. We took particular note of a couple absentees from the hall – for a start, Roche and obesity drug companies (aside from Novo Nordisk) – which we assume reflect both the challenging SMBG and obesity environments in the US and perhaps a different perception on the return on investment from exhibit hall booths. In the modern era of digital and social media marketing, an argument could be made that the ROI of exhibit hall booths is a bit hard to measure. Our coverage includes the following companies and organizations: Abbott, Alere, Amgen, Ascensia, AstraZeneca, Becton Dickinson, BI/Lilly, Dexcom, Glooko, GSK, InSpark, Insulet, Intarcia, J&J/Animas, J&J/LifeScan, J&J/Janssen, LabStyle, Lilly, Mannkind, Medtronic, Merck, Novo Nordisk, Novo Nordisk (Saxenda), Sanofi, Sanofi-Regeneron, Takeda, Tandem, Valeant, and Valeritas.

Historical Visits in the New Orleans Area

  • In between our diabetes learnings, our team took the time to visit two of the New Orleans area’s most important and informative historical sites: (i) the Whitney Plantation and (ii) the National WWII Museum. 
    • We toured the Whitney Plantation, a former sugarcane plantation and the only museum in Louisiana to take a direct focus on slavery. The Whitney Plantation tour featured powerful storytelling drawn from the narratives of men and women who had been emancipated from slavery as children and young adults. After exploring the unsettling scenery of an old slave jail, restored slave cabins, and a church built by former slaves, our team agreed that the Whitney taught us more about the hateful atrocities of slavery than we had ever collectively learned in school. In connecting the dots back to our work at Close Concerns, we reflected on the racial disparities we continue to see in diseases like diabetes and obesity. This experience has thus pushed us to more deeply consider how slavery and its successor systems have contributed to the massive inequities that we continue to see in healthcare access and quality of care today
    • In addition, our team visited the National WWII Museum, which builds on the individual narratives of the American military in World War II. The museum was built as a testament to the 16 million veterans who served in World War II, of whom only ~850,000 are still alive. Visitors are given dog tag keycards that they can scan at different points during their trip through the museum and learn the real-life stories of Americans throughout the world. Mixed in with the panels on the overall history of the war are pieces dedicated to the wartime experiences of people like Slaughter-House Five author Kurt Vonnegut, plus the many men and women whose names are otherwise lost to history. As we returned to the world of diabetes, we at Close Concerns reflected upon the salient connection between the present diabetes epidemic and the history we learned at the National WWII Museum: the US Department of Veterans Affairs reports that nearly a quarter of all veterans have diabetes. While the reason for this disproportionate incidence of diabetes remains unclear, hypotheses include the veteran population’s overall lower incomes, reduced access to healthy food, and higher rates of obesity and war-related exposure to environmental toxins.

-- by Melissa An, Adam Brown, Abigail Dove, Helen Gao, Varun Iyengar, Brian Levine, Payal Marathe, Sarah Odeh, Emily Regeir, Ava Runge, and Kelly Close